The present invention relates generally to degradable hydrogels and more specifically to degradable poly(vinyl alcohol) (PVA) hydrogels that are suitable for use as biomaterials.
Biocompatible hydrogels have become a favored material for many biomedical applications. In many cases, it is preferable to employ a hydrogel that is biodegradable so that the body can rid itself of the foreign material over a period of time. One biodegradable hydrogel is disclosed in U.S. Pat. No. 5,410,016 to Hubbell et al. This material is made from biodegradable, polymerizable macromers having a water soluble region, at least one degradable region which is hydrolyzable under in vivo conditions, and free radical polymerizable end groups having the capacity to form additional covalent bonds resulting in macromer interlinking, wherein the polymerizable end groups are separated from each other by at least one degradable region. In preferred embodiments, the macromers include a central backbone of polyethylene glycol flanked by degradable regions of polycaprolactone or polylactide, which are in turn flanked by polymerizable vinyl groups.
A primary disadvantage of the macromers and hydrogels disclosed by Hubbell is that they are inflexible in design. PEG has only two groups which are easily modified, the terminal hydroxyl groups, and those groups are modified with the biodegradable and polymerizable groups. Moreover, Hubbell does not disclose any ways in which the macromers can be modified or in which the hydrogel can be modified after its formation. Also, the degradable PEG material developed by Hubbell et al. exhibits a large degree of swelling in aqueous solutions, which is disadvantageous in many applications.
PVA based hydrogels are disclosed in U.S. Pat. Nos. 5,508,317 and 5,932,674 to Muller. However, these hydrogels are not degradable.
PVA hydrogels offer many advantages over PEG based hydrogels. For example, the availability of pendant OH groups along a PVA backbone adds versatility in terms of the various modifications that could be made to the macromer (e.g. attachment of degradable segments, active agents, hydrophobic groups, etc).
Moreover, a PVA system with its pendant OH groups allows for variations in loading (density) of the attached groups, and this is an important feature to have in a macromer. Third, PEG hydrogels are noted for their superior swelling in aqueous environments. This swelling property could be undesirable for certain applications. With a PVA hydrogel, the choice of a suitable PVA (with appropriate attached groups if desired) can yield a non-swellable, minimally swellable, or even shrinkable system.
Fourth, PVA possesses greater adhesive properties than PEG. This might be desirable for certain applications. Furthermore, PVA due to its hydrocarbon backbone has greater oxidative stability than PEG and it can be stored as aqueous solutions as opposed to PEG that has to be stored as a freeze-dried powder.
Lastly, the preparation of a PVA macromer can be done in aqueous medium with a final ultrafiltration step for purification. As opposed to this, PEG-based acrylates/methacrylates are prepared in organic solvents, and if not purified well can have toxic residuals such as triethylamine hydrochloride.
A disadvantage of the PVA hydrogels that have been developed is that they are not degradable. Accordingly, it would be advantageous to have a PVA hydrogel that is degradable and methods for making such hydrogels. Moreover, it would be advantageous to have a degradable hydrogel having multiple pendant groups that allow for the attachment of various modifiers.
The invention is directed to biodegradable biocompatible hydrogels based on poly(vinyl alcohol) and methods for their preparation. The degradable hydrogels can be formed in vivo or ex vivo. The hydrogels can be used for a number of biomedical applications, including, but not limited to, implants, embolic agents, wound healing dressings, adhesion prevention, sealants, bulking agents, coatings for biomaterials, and delivery of biologically active compounds such as drugs, genes, proteins, and enzymes. The hydrogels are advantageous in that the PVA backbone can be easily modified and can provide hydrogels having very different properties.
The methods for preparation of the hydrogels involve the use of prepolymers. The prepolymers have a PVA backbone and pendant chains that include a polymerizable group. In one embodiment, the pendant chains also include a biodegradable region. In another embodiment, biodegradable regions are incorporated into the hydrogel during its formation.
In a first general embodiment, a PVA prepolymer having crosslinkable groups and a second component having a degradable region flanked by crosslinkable groups are combined under conditions suitable for crosslinking the groups. The resulting hydrogel that is formed contains PVA chains linked by degradable regions.
In a second general embodiment, PVA prepolymers are formed having pendant crosslinkable groups separated from the PVA backbone by a biodegradable region. Hydrogels are formed by exposing the prepolymers to conditions that initiate crosslinking of the crosslinkable groups.
The many pendant hydroxyl groups of PVA allow great versatility in design of hydrogels with desired characteristics. Suitable hydrogels can be formed without having to employ each of the hydroxyl groups for attaching crosslinkable groups. Certain hydroxyl groups can be modified before the prepolymer is formed, after the prepolymer is formed, or even after the hydrogel is formed.